Despite advances in the management of sepsis patients, a large number of those patients die from the ensuing septic shock and multiple organ failure. Thus, there is an urgent unmet medical need for a novel and effective therapy for sepsis. Excessive recruitment of activated neutrophils into various tissues is a major contributing factor for organ injury in sepsis. In the previous cycle of this project, we have demonstrated the beneficial effect of milk fat globule epidermal growth factor-factor VIII (MFG-E8) in reducing inflammatory responses and organ injury, and improving survival in an animal model of sepsis induced by cecal ligation and puncture (CLP). We have recently discovered a novel property of MFG-E8 in inhibiting the infiltration of activated neutrophils into tissues. By analyzing the proten structure of human MFG-E8 for its binding to integrins, we have screened a large number of human MFG-E8-derived peptides. We have identified a short peptide, named MSP68, which inhibited neutrophil adhesion and migration. In this renewal application, we will focus on further characterization of MSP68 in alleviating tissue injury in sepsis and the development of MSP68 as a new anti-sepsis therapy. Post-treatment with MSP68 significantly decreased the inflammatory responses and attenuated organ damage in sepsis mice induced by CLP. MSP68 treatment reduced the number of neutrophils infiltrating into the lungs and liver of sepsis mice. The ten-day survival of sepsis mice was markedly improved with MSP68 treatment. MSP68 had a direct effect on regulating neutrophil adhesion and chemotaxis. Using surface plasmon resonance (SPR) analysis, we further demonstrated that MSP68 bound to integrins directly. Based on these novel findings, we hypothesize that the human MFG-E8-derived peptide MSP68 inhibits neutrophil infiltration into tissues during sepsis, leading to the attenuation of tissue ijury and improvement in survival of sepsis animals. Accordingly, three specific aims are proposed: (1) to further investigate the role of MSP68 in inhibiting neutrophil infiltration in sepsis; (2) t determine the molecular mechanism responsible for such an inhibitory effect of MSP68; and (3) to evaluate the efficacy and safety of MSP68 as a therapeutic agent for sepsis. The proposed studies will lead to a new direction for the development of innovative therapeutics for patients with sepsis. Through this innovative research, it is expected that MSP68 will be developed as a novel drug to treat sepsis and septic shock.